The candidate is M.D./Ph.D. who will have completed the clinical requirements of his residency in clinical pathology at Brigham and Women's Hospital prior to the proposed start date. He is committed to a career as a biomedical researcher in academic medicine, and has a particular interest in the biology of senescence. He has worked previously in the fields of molecular biology, the biochemistry of transcription and Drosophila developmental biology, and now wishes to learn more about experimental approaches to the study of aging. He also wishes to further develop the skills he will need to become an independent investigator. The proposed research will be carried out primarily in the laboratory of Dr. Leonard Guarente at M.I.T, who has engaged in detailed genetic and molecular investigations of aging in yeast for five years, and has expanded into studies in mouse and humans in the past two. Dr. Jeanne Wei, of the Harvard Division on Aging, will comentor the candidate, providing expertise on studies of aging in humans. The candidate will also participate in the regular activities of the Division on Aging. The candidate proposes two main investigations. First, to characterize the biochemical activities of the protein that is mutated in Werner's syndrome (WRN). The probable helicase activity of WRN will be defined and functional interactions with other proteins, including single stranded DNA binding proteins and topoisomerases, will be examined. Attempts will be made to define direct roles of WRN in simple recombination and transcription systems. The second part of the proposal is to examine the role of changes of ribosomal DNA (rDNA) metabolism in Werner's syndrome and in natural aging in humans and mice. Age-related changes in rDNA quantity, structure, and transcription in humans and mouse models will be examined. Finally, attempts will be made to determine the functional significance of these changes.